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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK

James S Foster1, Romaine I Fernando, Noriko Ishida

  • 1Department of Obstetrics and Gynecology, Graduate School of Medicine, Program in Comparative and Experimental Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, USA.

The Journal of Biological Chemistry
|August 9, 2003
PubMed

Insights

Estrogen down-regulates p27Kip1 in breast cancer cells via Skp2-dependent and -independent pathways. Subcellular localization of p27Kip1 and the ERK pathway are crucial for this process.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • p27Kip1 is a key regulator of mammary epithelial growth and breast cancer.
  • p27Kip1 levels are controlled by proteolysis, influenced by CDK2 and Skp2.
  • Estrogen's role in p27Kip1 regulation in MCF-7 cells requires further investigation.

Purpose of the Study:

  • To investigate the roles of Skp2 and p27Kip1 subcellular localization in estrogen-induced p27Kip1 down-regulation in MCF-7 cells.
  • To elucidate the involvement of the ERK signaling pathway in this regulatory process.

Main Methods:

  • MCF-7 cells were treated with 17beta-estradiol and antiestrogens.
  • Experiments involved G1 blockade (p16Ink4a, roscovitine), Skp2 manipulation (overexpression, antisense), CRM1 inhibition (leptomycin B), and p27Kip1 mutation (S10A).
  • ERK pathway activation was studied using Raf-1caax and pathway blockade.

Main Results:

  • Estrogen increased Skp2, but p27Kip1 down-regulation persisted even with G1 blockade.
  • p27Kip1 stabilization occurred with inhibition of nuclear export or specific mutation, and was prevented by Skp2 inhibition.
  • ERK pathway activation led to cytoplasmic p27Kip1 localization and degradation, independent of Skp2, while pathway blockade prevented these effects.

Conclusions:

  • Estrogen-induced p27Kip1 down-regulation in MCF-7 cells involves both Skp2-dependent and -independent mechanisms.
  • Subcellular localization of p27Kip1 is critical for its regulation by estrogen.
  • The Ras/Raf-1/ERK signaling pathway is essential for estrogen's control over p27Kip1 levels and localization.

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